Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body:
1. Increased rate of protein synthesis in all cells of the body; PA1 2. Decreased rate of carbohydrate utilization in cells of the body; PA1 3. Increased mobilization of free fatty acids and use of fatty acids for energy. PA1 Bu butyl PA1 Bn benzyl PA1 BOC, Boc t-butyloxycarbonyl PA1 BOP Benzotriazol-1-yloxy tris/dimethylamino)phosphonium hexafluorophosphate PA1 calc. calculated PA1 CBZ, Cbz Benzyloxycarbonyl PA1 DCC Dicyclohexylcarbodiimide PA1 DMF N,N-dimethylformamide PA1 DMAP 4-Dimethylaminopyridine PA1 EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride PA1 EI-MS Electron ion-mass spectroscopy PA1 Et ethyl PA1 eq. equivalent(s) PA1 FAB-MS Fast atom bombardment-mass spectroscopy PA1 HOBT, HOBt Hydroxybenztriazole PA1 HPLC High pressure liquid chromatography PA1 KHMDS Potassium bis(trimethylsilyl)amide PA1 LAH Lithium aluminum hydride PA1 LHMDS Lithium bis(trimethylsilyl)amide PA1 Me methyl PA1 MF Molecular formula PA1 MHz Megahertz PA1 MPLC Medium pressure liquid chromatography PA1 NMM N-Methylmorpholine PA1 NMR Nuclear Magnetic Resonance PA1 Ph phenyl PA1 Pr propyl PA1 prep. prepared PA1 TFA Trifluoroacetic acid PA1 THF Tetrahydrofuran PA1 TLC Thin layer chromatography PA1 TMS Tetramethylsilane
A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carded with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. The instant compounds are non-peptide analogs for promoting the release of growth hormone which are stable in a variety of physiological environments and which may be administered parenterally, nasally or by the oral route.